Abstract
Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (TH2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated TH2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell–intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow–resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to TH2 cytokine–dependent inflammation and allergic disease.
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Acknowledgements
We thank members of the Artis lab for helpful discussions; M.R. Comeau (Tslp−/− mice, Amgen), H. Oettgen (Igh-7−/− mice, Harvard University) and J. Weiser (Nod1−/− mice, University of Pennsylvania) for providing access to mice; L. Shawver, R. Sinha and R. Custers-Allen for assistance with data; J. Sawalle-Belohradsky and B. Hagl for performing DOCK8 sequencing; A. Jansson, G. Notheis, B.H. Belohradsky, M. Albert and the referring physicians for patient care; the Matthew J. Ryan Veterinary Hospital Pathology Lab; the National Institute of Diabetes and Digestive and Kidney Disease Center for the Molecular Studies in Digestive and Liver Disease Molecular Pathology and Imaging Core (DK50306); the Abramson Cancer Center Flow Cytometry and Cell Sorting Resource Laboratory (supported by US National Cancer Institute Comprehensive Cancer Center Support grant (2-P30 CA016520) for technical advice and support; and the University of Pennsylvania Gnotobiotic Mouse Facility for germ-free mice. Research in the Artis lab is supported by the US National Institutes of Health (AI061570, AI087990, AI074878, AI095608, AI083480 and AI095466 to D.A.; T32-AI060516 to D.A.H.; F32-AI085828 to M.C.S.; T32-AI05528 to M.C.A.) the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award (D.A.), the Penn Genome Frontiers Institute (D.A. and F.D.B.), and pilot grants from the University of Pennsylvania Veterinary Center of Infectious Diseases (D.A.). Additional National Institutes of Health support provided by HL107589 and HL111501 to T.K., AI067946 to J.S.O. and UH2DK083981 to F.D.B.
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D.A.H., M.C.S., M.C.A., B.S.K., D.K. and D.A. designed and performed the research; D.F.L., E.D.R., J.S.O., M.K., T.K. and F.D.B. provided reagents; D.A.H., M.C.S., M.C.A., B.S.K. and D.A. analyzed the data; D.A.H., M.C.S. and D.A. wrote the manuscript.
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Hill, D., Siracusa, M., Abt, M. et al. Commensal bacteria–derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 18, 538–546 (2012). https://doi.org/10.1038/nm.2657
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DOI: https://doi.org/10.1038/nm.2657
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